U.S. Pat. No. 5,382,600 involves crude forms of racemic 3,3-diarylpropylamine as having formula I:
wherein R1 is hydrogen or methyl, R2, R3 and R4 independently are hydrogen, methyl, methoxy, hydroxy, carbamoyl, sulphamoyl or halogen and R5 and R6 independently are C1-C6 alkyl, which may be joined to form a non-aromatic ring having no heteroatom other than the amine nitrogen and each of which may carry a hydroxy substituent or adamantyl, and wherein R5 and R6 together contain at least four carbon atoms and include the salts formed with physiologically acceptable acids.
Chemically, tolterodine tartrate is (R)—N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine L-hydrogen tartrate, also known as 2-((R)-3-di-isopropylamino-1-phenyl-propyl)-4-methyl-phenol (2R,3R)-2,3-dihydroxybutanedioate having structural Formula Ia; see U.S. Pat. No. 5,382,600.

A process for preparing tolterodine was mentioned in U.S. Pat. No. 5,382,600. The process starts from 6-methyl-4-phenyl-3,4-dihydrocoumarin of structural Formula II.
which by a sequence of reactions is converted into racemic tolterodine HCl ¼H2O (see Example 9c of U.S. Pat. No. 5,382,600). According to Example 22 of U.S. Pat. No. 5,382,600 the racemic tolterodine HCl ¼H2O is resolved with L-(+) tartaric acid to give crude (R)-tolterodine L-hydrogen tartrate which must be recrystallized twice from EtOH to yield “pure” (R)-tolterodine L-hydrogen tartrate having [α]25546 (5%, MeOH) of +36.0°.
U.S. Pat. No. 5,922,914 refers to an alternative process for the preparation of tolterodine. According to Examples 4 or 5 of U.S. Pat. No. 5,922,914 racemic tolterodine HCl is basified and extracted in organic solvent resulting in racemic tolterodine base. The organic solvent is evaporated to yield a residue (i.e. not a solid or crystalline form) of racemic tolterodine base. The residue of racemic tolterodine base is then dissolved in ethanol and treated with L-(+) tartaric acid to give crude (R)-tolterodine L-hydrogen tartrate which must be recrystallized twice from EtOH or from MeOH/acetone to yield “pure” (R)-tolterodine L-hydrogen tartrate having [α](1%, MeOH) of +27.4°.
International patent application WO 01/49649 refers to a process for the enantioselective preparation of tolterodine, which consists of the preparation of an enantiomerically enriched compound of formula II (as described above), starting from a compound of formula III and performing an enantioselective reduction to obtain an enantiomerically enriched compound of formula IV, which by means of a sigmatropic rearrangement is converted to an enantiomerically enriched compound of formula V, which is finally oxidized by means of a Baeyer-Villiger reaction to yield an enantiomerically enriched compound of formula II.

Examples 4, 5 and 6 of WO 2004/078700 refer to a conversion of tolterodine HBr into crude tolterodine tartrate which is recrystallized from MeOH to yield pure (R)-tolterodine L-hydrogen tartrate e, but discloses no data regarding its enantiomeric purity. It is recognized in the art that (R)-tolterodine L-hydrogen tartrate shows polymorphism (see WO 04/089281).
U.S. Pat. No. 6,822,119 refers to an improved process for the preparation of tolterodine. The process starts from a compound of formula II as described above (6-methyl-4-phenyl-3,4-dihydrocoumarin—referred to as 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran 2-one in the '119 patent), which by a sequence of reactions is converted into racemic tolterodine HBr. However, there is no mention about the resolution of racemic tolterodine HBr for producing (R)-tolterodine L-hydrogen tartrate.
International patent application WO 05/005356 involves the preparation of tolterodine base isomer by enantioselective hydrogenation of a precursor thereof. A preferred embodiment of that patent application is the preparation of enantiomerically enriched compound of formula II as described above starting with 6-methyl-4-phenylcoumarin.
Racemic forms of 3,3-diarylpropylamine compounds, e.g., tolterodine, have not been obtained with sufficient purity or in crystalline form. Racemic tolterodine in its free base form (“racemic tolterodine”) has not been previously obtained with sufficient purity or in crystalline form. As such, the racemic 3,3-diarylpropylamine free base and tolterodine free base have been unsuitable for characterization by X-ray crystallography, differential scanning calorimetry and/or by IR. Additionally, the low degree of purity of these precursor racemic 3,3-diarylpropylamino compounds or racemic tolterodine free base compound results in lower degrees of purity for the (R)-tolterodine L-hydrogen tartrate upon conversion of the precursor compound to the tartrate salt. Accordingly, there are problems in preparing 3,3-diarylpropylamine compounds, e.g., tolterodine.
Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.